Regulation of levels of various neurochemicals and other chemicals in the central and peripheral nervous system is likely to provide a critical mechanism for the treatment and/or prevention of neurodegenerative and psychiatric diseases in humans.
For purposes of this document, Neurochemical refers to a chemical substance released from or which acts on neurons and/or glia during, or as a result of, neurotransmission or neurosecretion. Neurochemicals include, but are not limited to neurotransmitters, neuromodulators, neuropeptides, and/or neuroregulators. Exemplary known neurochemicals include dopamine, acetylcholine, glutamate, norepinephrine, epinephrine, serotonin, and their precursors and metabolites (e.g., L-DOPA and DOPAC, respectively). The central nervous system may include, but is not limited to, structures in the brain (including the spinal cord) such as the thalamus, substantia nigra pars compacta and pars reticulata, cerebral cortex, caudate-putamen, globus pallidus, cerebellum, limbic structures, cranial nerve nuclei, and brain stem. The peripheral nervous system refers to peripheral ganglia of the somatic and/or autonomic nervous system, such as, but not limited to, spinal ganglia, enteric ganglia, and cardiac ganglia. The peripheral nervous system, as used herein, also refers to the target organs of the peripheral autonomic nervous system, including, but not limited to, the adrenal gland, carotid body, and smooth muscle.
Concentrations of neurochemicals are altered in many disease states, including psychiatric disorders and some neurodegenerative diseases, including some movement disorders such as Parkinson's Disease (PD). Many medications used to treat these disorders affect neurochemical levels within the central nervous system, and it is believed that their effectiveness is a consequence of their effect on those neurochemical levels. For example, both Tricyclic Antidepressents and Selective Serotonin Reuptake Inhibitors (SSRI's) have an effect of increasing serotonin levels and are commonly used to treat depression, among other conditions. Similarly drugs that affect dopamine levels, including the dopamine-precursor drug L-DOPA, are commonly used to treat PD, among other conditions. Even amphetamine has an effect on neurochemical concentrations; its effect on wakefulness is believed to be due to its effect on norepinephrine, serotonin, and dopamine levels in the brain.
Patients suffering from tremor and other symptoms of PD, and similar conditions, may undergo surgery to lesion a part of the brain (e.g., the ventral intermediate (Vim) nucleus of the thalamus the internal segment of the globus pallidus (GPi) (FIG. 1), or the subthalamic nucleus (STN)), which in some cases may afford some relief. Such a lesion is, however, irreversible, placement and size of the lesion can be difficult to control precisely, and such lesions may in some cases lead to permanent side effects. It is desirable to be able to produce relief in a reversible manner such that possible disability due to such permanent side effects may be avoided.
It has been proposed that some of these conditions can be treated by applying drugs or electrical stimulation directly into areas of the brain that are involved in these conditions. For example, Whitehurst, US 2007/0100393, paragraph 36, refers to “infusion of one or more drugs at the stimulation site and/or applying one or more electrical current pulses to the stimulation site.” The one or more stimulation sites referred to in Whitehurst “may include . . . the [nucleus of the solitary tract] NTS, the ventral intermediate thalamic nucleus, the GPi, the [external segment of the globus pallidus] GPe, the STN, the pallido-subthalamic tracts, the substantia nigra pars reticulare, the pallido-thalamic axons, the putamen (Put) to GPe fibers, the subthalamopallidal fibers, the putamen to GPi fibers, the cerebellum, and/or any other suitable location within the brain.” Whitehurst, however, fails to describe treatment of a motor disorder through using a neurochemical-sensitive chemosensor to provide feedback control of stimulation of another part of the brain.
It is known in the art that electrical stimulation of deep brain structures is capable of treating the symptoms of some diseases, such as Parkinson's Disease (see, e.g., Benabid et al, 2000 Neurology, 55:s40-44, see also, Obeso et al, Deep-Brain Stimulation Of The Subthalamic Nucleus Or The Pars Interna Of The Globus Pallidus In Parkinson's Disease, N Engl J Med, Vol. 345, No. 13, Sep. 27, 2001, 957-963).
Precise electrode placement in small, deep, neurological structures like the STN can be difficult to achieve. Further, subjects often have differing degrees of disease; subjects may often have different degrees of disease between left and right structures in the same brain. In consequence, open-loop deep-brain stimulation devices are difficult to adjust for optimum effectiveness.
While devices having the ability to measure release of neurochemicals as evoked by electrostimulation in particular brain regions are known (see, e.g., Dugast et al., 1994 Neuroscience 62:647), the known art fails to teach a method or device that utilizes such information to initiate or automatically adjust electrical deep brain stimulation (DBS) treatment of PD in an individual using a chemosensor in one part of the brain to control stimulation in another part of the brain to treat a specific disorder.
Whitehurst, US 2007/0100393 A1, discusses treatment of movement disorders through a device implanted or partially-implanted in a subject that provides brain stimulation, paragraph 74, and suggests generally that it may be appropriate to monitor pH, muscle electromyographic data, head or limb accelerations, or to use electroencephalographic data to provide control information for a brain stimulator.
Implantable, open-loop, stimulators intended for long-term use are known in the art. For example, the Medtronic ® Activa RC 37612 provides for stimulation on one or two leads with through-skin programmability. Medtronic is a trademark of Medtronic, Inc., Minneapolis, Minn. The Activa RC 37612 provides for pulse widths of 60 to 450 microseconds and pulse rates of 2 to 250 Hz, with pulse voltage in voltage mode programmable from 0 to 10.5 volts in 0.05 volt steps or current in current mode programmable from 0 to 25.5 milliamps in 0.1 milliamp steps. Typical available neurostimulators do not have automatic feedback control and require extensive testing and calibration. These commercially available neurostimulators are provided with stimulus lead, or electrode, assemblies typically having four electrodes near their tips, and the stimulator may be programmed to use different combinations of the electrodes.